Project Summary Multiple Myeloma (MM) is an incurable plasma cell malignancy affecting >30,000 new patients per year. All active MM patients have a preceding phase of smoldering MM (SMM) with clonal plasmacytosis similar to active MM, but without end organ damage. The risk of progression for SMM patients to active MM is 10% or higher per year. There are no currently approved therapies for SMM and these patients are excellent candidates for chemoprevention trials. Our clinic sees more than 80 SMM patients per year and we have several ongoing trials studying PD-1/PD-L1 blockade in relapsed MM. We hypothesize that peptides corresponding to Mutation-derived Tumor Neoantigens (MTA) can be immunogenic and augment T-cell activation by immune checkpoint (PD-1/PD-L1) blockade in SMM. Our preliminary results show frequencies of 200-500 MTAs per active MM patient, providing a rationale for studying MTA-based vaccination in SMM. We will conduct an in-depth analysis of SMM tumor immunology including neo-antigenic landscape and T cell responsiveness using the immunogenicity analysis and ex vivo validation of mutation derived SMM antigens. Our preliminary studies using primary samples from MM patients treated with checkpoint inhibitors demonstrate a significant increase in T-cell responses to MTAs. We will investigate the merit of combining immune checkpoint inhibitor(s) with MTA-based peptides versus single-agent MTA to augment T-cell responses in T cells from SMM patient samples. Our long term goal is to develop a combination therapy of immune checkpoint blockade with effective MTA-based personalized vaccines administered early in the disease trajectory, i.e. at SMM, deferring progression to active MM and ultimately increasing survival in this fatal disease.